17-47283411-TG-T

Position:

• chr17-47283411-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000212.3(ITGB3):​c.224del​(p.Cys75LeufsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB3 NM_000212.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 10.0

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-47283411-TG-T is Pathogenic according to our data. Variant chr17-47283411-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 953063.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGB3	NM_000212.3	c.224del	p.Cys75LeufsTer10	frameshift_variant	3/15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.224del	p.Cys75LeufsTer10	frameshift_variant	3/15	1	NM_000212.3	ENSP00000452786	P1
ITGB3	ENST00000571680.1	c.224del	p.Cys75LeufsTer10	frameshift_variant	3/9	1		ENSP00000461626
ITGB3	ENST00000696963.1	c.224del	p.Cys75LeufsTer10	frameshift_variant	3/14			ENSP00000513002

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251424 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Sep 04, 2020

The ITGB3 c.224del (p.Cys75Leufs) frameshift variant has been reported homozygous in at least 2 GT probands (PMIDs: 25728920, 12083483). It is predicted to undergo NMD due to creation of a premature stop codon in exon 3. The overall allele frequency in gnomAD is extremely low at 0.000003977, with a MAF of 0.000008795 in the non-Finnish European population. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PVS1,PM2_supporting, PM3, and PP4_strong. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs753932639; hg19: chr17-45360777;